[Buster]

Without a doubt, one of the coolest papers I've seen recently -- and I've read a bunch. It explains and documents (with movies) how T-cells can cross the blood-brain barrier. This should have huge impact on MS, SC and frankly on PANDAS too.

kim you are going to LOVE this one. Wow.

Buster


http://www.nature.com/nature/journal/v462/...ature08478.html

Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions
Nature 462, 94-98 (5 November 2009) | doi:10.1038/nature08478;

The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks1. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce proinflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.


Translation (by Buster):

The blood brain barrier keeps out white blood cells and other large items such as proteins, nucleic acids, carbohydrates, and lipids (fats) that are circulating in the blood stream. However, the blood brain barrier is vulnerable to autoimmune attacks. Using a really cool technology, we studied rats that have a weakened blood-brain barrier and made a video of how T-cells interact with the blood-brain barrier. The T-cells can squeeze through the BBB (diapedesis) and once on the other side encountered macrophages and phagocytes that had found bacteria (antigens) and other stuff (including myelin proteins). The phagocytes showed parts of these antigens to the T-cells and the T-cells recognized some of the fragments as "foreign" and produced inflammation chemicals. The inflammation caused a breach in the blood-brain barrier.

To see the movies:

http://www.nature.com/nature/journal/v462/...ature08478.html

[mom md]

Very cool. We are now officially geeks though that we get so much enjoyment out of a scientific paper.

[Buster]

mom md, on Nov 25 2009, 06:47 PM, said:

Very cool. We are now officially geeks though that we get so much enjoyment out of a scientific paper.

Y'a know it, but of course I was officially a geek a long time ago :-)

Happy Thanksgiving.

[Buster]

Buster, on Nov 25 2009, 05:09 PM, said:

Translation (by Buster):

The blood brain barrier keeps out white blood cells and other large items such as proteins, nucleic acids, carbohydrates, and lipids (fats) that are circulating in the blood stream. However, the blood brain barrier is vulnerable to autoimmune attacks. Using a really cool technology, we studied rats that have a weakened blood-brain barrier and made a video of how T-cells interact with the blood-brain barrier. The T-cells can squeeze through the BBB (diapedesis) and once on the other side encountered macrophages and phagocytes that had found bacteria (antigens) and other stuff (including myelin proteins). The phagocytes showed parts of these antigens to the T-cells and the T-cells recognized some of the fragments as "foreign" and produced inflammation chemicals. The inflammation caused a breach in the blood-brain barrier.

I found another person had done a nice translation of this paper. See http://www.rdmag.com/News/2009/11/Life-Sci...vade-the-brain/

Buster

[KeithandElizabeth]

Hi Buster:

So, if you were to guess about my "non-PANDAS" 10 year old daughter with the high CAM Kinase II (171%), would you just say that her numbers were elevated due to recent strep infections and that her BBB remained closed? And then should these numbers just go down on their own without any treatment? Her other numbers, especially the anti-Tubulin(4x normal range) were also high. I know we are all just learning here and the Cunningham test is still in study mode. I wonder if any other children who did not have PANDAS symptoms, but were recently exposed to strep have taken this test?

I am just continually worrying about her and always trying to figure this whole illness out.

Elizabeth

[Buster]

Hi Elizabeth,

Yes, I do think that the key is whether the blood-brain barrier opens or not. I think you need all three events:

• The initiating strep infection,
  
• the unusual immune system response,
  
• and the breach of the BBB.

I think we'll find lots of kids get #1 and #2 without having #3. With respect to controls, I too think this is the area that will need careful study. Right now we have numbers but no clear understanding of what the number means. We might be measuring a side effect rather than a cause.

One of my old teachers was telling me about his search for causes of certain cardiac diseases and he thought he had found that certain patients had lower temperatures -- instead he found that the non-controls were being wheeled through a cold part of the hospital. Essentially until we know why something happens, the number is just a number.

At present, having a parent on this forum seems to cause elevated CaM Kinase II scores (that's a joke).

Buster

KeithandElizabeth, on Nov 25 2009, 09:16 PM, said:

Hi Buster:

So, if you were to guess about my "non-PANDAS" 10 year old daughter with the high CAM Kinase II (171%), would you just say that her numbers were elevated due to recent strep infections and that her BBB remained closed? And then should these numbers just go down on their own without any treatment? Her other numbers, especially the anti-Tubulin(4x normal range) were also high. I know we are all just learning here and the Cunningham test is still in study mode. I wonder if any other children who did not have PANDAS symptoms, but were recently exposed to strep have taken this test?

I am just continually worrying about her and always trying to figure this whole illness out.

Elizabeth

[peglem]

Quote

I found another person had done a nice translation of this paper. See http://www.rdmag.com...vade-the-brain/

Oh, thank God! I'm just a wanna be geek! I found the abstract and pictures interesting, but now that I understand them...WOW!

Quote

Quote

At present, having a parent on this forum seems to cause elevated CaM Kinase II scores smile.gif (that's a joke).

Aaah, good point!

[SF Mom]

Buster, When I saw Dr. Lewis he said he just received a grant to study T Cells.....

Once I receive my younger son's IgG Subclass results I intend to make the rounds with Margo and then Lewis again. It will be interesting what he has to say about Romy deficiencies. So far, low red blood cell count, low white blood cell count, deficiencies in 13 of 14 strep antibody titers.

I imagine you to work at LHM or SRI.

-Wendy

[kim]

a 24 lb turkey and 10 side dishes along with Fc regions/receptors and sialic acid still swirling in my pea brain, I'm really trying to process this in any spare moment.

just a couple of quick thoughts:

What's different about the vessels of the CNS that allows the T cells to start sticking?

If these aggressive T cells are actually able to creep against the current, it occurs to me that the bbb isn't really as "open" as I had imagined. It's the capabilty of the "possesed" T cell that's really the trouble maker?

What would happen if they added a little NAG to these T cells, if it has such "stunning" results against autoimmunity...would they stick, creep and invade? One of the concerns of using NAG was an "open," bbb regarding treatment of MS.

Are the phagocytes somehow signaling the T cells, hence their determination? It didn't really sound like there was an abnormal population of phagocytes in the area where the crossing took place?

If these questions signal "ignorance," remember I'm not any where near as geeky as Buster and MomMD and I bet my annual income reflects it!

[Buster]

kim, on Nov 26 2009, 09:56 AM, said:

What's different about the vessels of the CNS that allows the T cells to start sticking?

From the paper it seems like LFA-1 (lymphocyte function-associated antigen 1) was implicated in recruiting the T-cells to the site. LFA-1 is produced by Eicosanoids and by Leukocytes that are on the "brain" side of the BBB. The endothelial cells then seem to present "footholds" known as ICAM-1 (intercellular adhesion molecule-1) on the inner surface of the bloood vessel (see fig22b ), and then the T-cell seems to squeeze through similar to the leukocytes (see fig22c).

My guess (no data/reference yet) is there is some chemical near the site of the macrophage on the brain side that has high concentration of the chemical near where the T-cell should push through.

Quote

If these aggressive T cells are actually able to creep against the current, it occurs to me that the bbb isn't really as "open" as I had imagined. It's the capabilty of the "possesed" T cell that's really the trouble maker?

I think it is still the permeability of the BBB. It is true that certain antibodies and MS medication seems to stop the creeping behavior and limit the ability of the T-cells to creep with the ICAM-1.

Quote

What would happen if they added a little NAG to these T cells, if it has such "stunning" results against autoimmunity...would they stick, creep and invade? One of the concerns of using NAG was an "open," bbb regarding treatment of MS.

I can't speak to NAG, but NAC seems to be studied and seems to down regulate the LFA-1

Quote

Are the phagocytes somehow signaling the T cells, hence their determination? It didn't really sound like there was an abnormal population of phagocytes in the area where the crossing took place?

I agree and think it likely that it is a chemical getting across the BBB that "attracts" the T-cells to use the ICAM-1 to try to find the source. I keep thinking of it like one of those tom and jerry movies where the scent draws them toward the source.

Buster

[peglem]

Okay, I'm going to take the risk here of sounding ignorant (no pain, no gain). So the macrophages and phagocytes are already inside the brain cavity? Then the Tcells cross over and the antibodies are made onsite? This is very different from the way I pictured it...thought the antibodies themselves were crossing over.

[Buster]

peglem, on Nov 27 2009, 10:46 AM, said:

So the macrophages and phagocytes are already inside the brain cavity?

Yes, there are macrophages and phagocytes on the brain side of the BBB. However, what's unusual about these cells is that they can present pieces of neuronal tissue sequences in addition to normal antigens.

Quote

Then the Tcells cross over and the antibodies are made onsite? This is very different from the way I pictured it...thought the antibodies themselves were crossing over.

I don't think we know yet. There are two good theories here:

• T-cells create a breach through which existing antibodies cross
  
• T-cells create a breach through which B-cells cross (creating antibodies)

What I got from their paper was that the effector T-cells seem to be attracted to weak spots in the BBB. The T-cell seeks out the weak spot using the footholds on the epithelial cells. When a T-cell slips through, it connects with one of these "brain-side" macrophages/phagocytes and gets activated. Once activated it releases more inflammatory cytokines recruiting still more T-cells to the spot. This causes more inflammation and essentially a breach in the BBB through which other cells/antibodies can cross.

I personally think (due to size) it is more likely that the pre-existing antibodies cross rather than the B-cell crossing.

What has been on my mind is that it seems equally plausible that one of the T-cells comes back across the breach and connects up with a B-cell causing more antibody production.

In theory, IVIG and combined PEX/IVIG should affect both #1 and #2. Plasmapherisis (i.e., without IVIG) would likely affect only #1.


What I was struggling with was "if we got rid of the strep, why is there still antibody production in the blood?"

There seem to be three explanations here:

• we didn't actually get rid of the strep and there is some still in the system
  
• the T-cells and B-cells are self activating and don't need the original antigen
  
• the macrophages present more neuonal tissue and the T-cells confuse this with strep and activate

All of these theories seem to have merit. The first is the paper by Kaplan around intracellular strep and how strep can act more like a virus (invading a cell and then bursting forth to reinfect). The second is from a paper by Voss http://www.jimmunol....rint/180/3/1362 indicating that T-cells can stay activated if they find cooperative B-cells. This is basically a failure of the B-regulatory/T-regulatory mechanism. The third seems supported by Kirvan's papers about the cross-reactivity with neuronal tissue.

The good news is that (with PANDAS) we don't seem to see demyelination, so it looks like there is antibody interference with neuronal tissue but not destruction of neuronal tissue. If it is #3, then it is limited to a few macrophages. It takes very little antigen to produce a lot of antibodies so any of the above would explain the scenario

This is a long way of saying that I think the Nature paper is significant and perhaps the explanation as to why IVIG, prednisone, and PEX break the cycle by reducing the inflammatory cytokines and letting the BBB close.

Buster

[peglem]

I'm glad Voss doesn't start with "K"!

Quote

When a T-cell slips through, it connects with one of these "brain-side" macrophages/phagocytes and gets activated. Once activated it releases more inflammatory cytokines recruiting still more T-cells to the spot. This causes more inflammation and essentially a breach in the BBB through which other cells/antibodies can cross.

Anybody know what happened w/ Swedo's study testing autistic CSF for cytokines, and treating with minocycline?

Quote

This is basically a failure of the B-regulatory/T-regulatory mechanism. The third seems supported by Kirvan's papers about the cross-reactivity with neuronal tissue.

Is there a lab test to show weakness/failure/malfunction of the T/B reg system?

Also, it seems (though dangerous and much more invasive) the Cunningham test would be more reliable if the sample was CSF instead of blood serum. She did use CSF initially, no?

[Buster]

peglem, on Nov 27 2009, 12:39 PM, said:

Anybody know what happened w/ Swedo's study testing autistic CSF for cytokines, and treating with minocycline?

as far as I know that trial is still ongoing http://clinicaltrial...how/NCT00409747

Quote

Also, it seems (though dangerous and much more invasive) the Cunningham test would be more reliable if the sample was CSF instead of blood serum. She did use CSF initially, no?

Yes, the early tests isolated the antibodies in the CSF for those patients who were in significant exacerbations. She also showed that such antibodies were absent during remission. It is not known whether the antibodies are a cause or a byproduct. They are correlated but not shown to be causal at this point.

Buster

[kim]

Buster, you're kinda like Santa Claus. Thanks as always, for all that you and EA mom share.

I see some of the info regarding NAC. Another thought that can't help but come to mind is that macrophages can eat metals.

I liked the Tom and Jerry analogy